CN111233877B - Galanthamine pamoate and preparation method thereof - Google Patents
Galanthamine pamoate and preparation method thereof Download PDFInfo
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- CN111233877B CN111233877B CN201811437827.3A CN201811437827A CN111233877B CN 111233877 B CN111233877 B CN 111233877B CN 201811437827 A CN201811437827 A CN 201811437827A CN 111233877 B CN111233877 B CN 111233877B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Abstract
The invention provides a galanthamine pamoic acid salt and a preparation method thereof, the compound has a structure shown in formula I, and has good dissolution characteristic and good stability, and a tablet prepared by using the compound as an active ingredient has slow dissolution performance and embodies an excellent slow release effect. In addition, the galanthamine pamoic acid salt provided by the invention is simple in preparation process, high in product yield and purity, and suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a galanthamine pamoic acid salt, a preparation method thereof and application thereof in pharmacy.
Background
Galantamine was first isolated from Galanthus australis, a plant of Amaryllidaceae, by Mashkovsky, a pathologist in Soviet Union. Galantamine as a second generation AchE inhibitor mainly acts on the catalytic site of AchE, and has the structure-activity relationship as follows: (1) hydroxyl in the molecular structure and Glu199 in the AChE form a hydrogen bond, and a double bond of a cyclohexene ring and Trp84 in the AChE form a p-p bond, so that the AChE is inhibited; (2) modification of N-terminal alkylation in a molecular structure is beneficial to approaching the bottom of a catalytic site of AchE, and plays a very important role in inhibiting the AchE.
The compound with the structure shown in the formula II is the parent structure of an acetylcholinesterase (AchE) inhibitor galanthamine, and has the chemical name: 1-methyl-3-methoxy-4 a,5,9,10,11, 12-hexahydro-6H-benzofuran [3a,3,2ef ] [2] benzazepin-6-ol. Galantamine as the second generation AchE inhibitor, approved by FDA for treating mild and moderate Alzheimer Disease (AD) in 2 months of 2001, has no hepatotoxic effect, and has a clinical effective rate of 60-70%. The current commercial dosage forms of galanthamine include galanthamine hydrobromide tablets, galanthamine hydrobromide sustained release capsules and galanthamine hydrobromide oral liquid. Due to the particularity of AD patients, the frequent administration times of the existing dosage forms cause the phenomenon that patients often take missed or multiple doses, and the ideal treatment effect cannot be achieved.
Galantamine is unstable in air and pharmaceutically acceptable salts of this compound are commonly used in formulations. The galanthamine salt compounds disclosed in the prior art only contain galanthamine hydrobromide. Chinese patent CN101080231B discloses a hydrobromide of galanthamine and a preparation method thereof. Galanthamine hydrobromide is very soluble in water,the maximum solubility reaches 35 mg.mL -1 Moreover, patent CN10762298 describes that galantamine hydrobromide is very easy to absorb moisture and form balls during storage, and the related substances have a growing tendency, and its unstable property and easy dissolution characteristics greatly limit its application as a sustained release preparation. The existing commercially available galanthamine sustained-release preparation is prepared by adding a large amount of sustained-release materials in a prescription, and it can be determined that the addition of the auxiliary materials can affect the properties of the active ingredients, such as the drug effect, to a certain extent, and the more the auxiliary materials in the preparation, the higher the potential hazard to the body of a user. Therefore, on the premise of not changing the pharmacodynamic structure of galanthamine, other pharmaceutically acceptable salts of galanthamine, especially a galanthamine salt compound with lower solubility and better stability in water, still need to be continuously researched to ensure that the drug has certain slow release characteristic, so that the dosage of auxiliary materials in a prescription is reduced, the activity of the drug is improved, and the potential hazard to a user is reduced as much as possible, so that the application of galanthamine in pharmacy is continuously expanded, and a better drug and better medication experience are provided for the patient.
Disclosure of Invention
Aiming at the problems of high solubility and poor stability of the existing galanthamine salt and galanthamine hydrobromide salt, the invention aims to provide the galanthamine pamoic acid salt with lower solubility, good light resistance and good stability.
In a first aspect of the invention, a galantamine pamoate compound is provided.
In a second aspect of the invention, a process for preparing a galanthamine pamoate compound is provided.
In a third aspect of the invention, there is provided a pharmaceutical composition comprising galantamine pamoate.
In a first aspect, a galantamine pamoate compound has a structure represented by formula I:
wherein n is 1 or 2.
Preferably, the galanthamine pamoate compound n shown in formula I is 1, i.e., galanthamine pamoate.
Preferably, the galantamine pamoate compound shown in the formula I has a nuclear magnetic resonance hydrogen spectrum shown in figure 1 when n is 1.
In a second aspect, a method for preparing a galanthamine pamoate compound specifically comprises the following steps: dissolving galanthamine hydrobromide in a certain organic solvent, dissolving pamoic acid in the same organic solvent, dropwise adding the solution into the galanthamine hydrobromide solution, heating and stirring until the reaction is finished, cooling and standing, and performing suction filtration to obtain galanthamine pamoate.
Preferably, the organic solvent is selected from one of or a mixed solvent of dimethyl sulfoxide, N-dimethylformamide, hexamethylphosphoric triamide and 1, 3-dimethyl-2-imidazolidinone solvent, wherein dimethyl sulfoxide and N, N-dimethylformamide are preferred.
Preferably, the mass-volume ratio of the galanthamine hydrobromide to the organic solvent is 1:10-50, g/mL; preferably 1:20-30, g/ml.
Preferably, the molar ratio of the galanthamine hydrobromide to the pamoic acid is 1: 1-5, and particularly preferably 1: 1-2.
Preferably, the reaction temperature is 0-100 ℃, preferably 15-60 ℃.
Preferably, the reaction time is 0.5 to 24 hours, preferably 2 to 10 hours.
Preferably, the cooling temperature is 0-15 ℃.
Preferably, the cooling mode is ice bath cooling or program cooling.
In a third aspect, a pharmaceutical composition comprising galantamine pamoate, the pharmaceutical composition comprising any of the galantamine pamoate salts described herein and other pharmaceutically acceptable components.
Preferably, the pharmaceutically acceptable component is selected from other combinable active ingredients, carriers, diluents, fillers, disintegrants, lubricants, binder colorants or combinations thereof.
Preferably, the pharmaceutical composition is a spray, a tablet, a capsule, a powder injection, a liquid injection and the like.
Compared with the prior art, the invention has the following technical effects:
1. the invention provides a novel galanthamine pamoic acid salt compound, wherein the N atom of galanthamine is combined with the carboxyl of pamoic acid through ionic bonds to form a novel galanthamine salt, and the compound has lower solubility and greatly improves the stability of galanthamine.
2. The invention provides a novel preparation method of galanthamine pamoate, which has the advantages of simple and feasible process, high product yield and high purity, and is suitable for industrial production.
3. The invention provides the galanthamine pamoic acid salt with excellent dissolution characteristic and stability, and provides a better raw material for preparing a long-acting sustained-release preparation of galanthamine.
Drawings
FIG. 1. Galanthamine pamoate 1 H NMR hydrogen spectrum.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are intended to be illustrative only and not to be limiting, and therefore, the present invention is intended to be simply modified within the scope of the present invention as claimed.
Example 1
Dissolving 1.14g of galanthamine hydrobromide in 25mL of dimethyl sulfoxide, dropwise adding 100mL of dimethyl sulfoxide solution containing 1.41g of pamoic acid, and stirring at 25 ℃ for reacting for 6 hours after dropwise adding; after the reaction is finished, cooling the reaction liquid to 0-5 ℃, standing for 24 hours at the temperature, carrying out vacuum filtration, and carrying out vacuum drying at 50 ℃ for 12 hours to obtain light yellow powder, wherein the yield is 78.55%, and the purity is 99.91%.
Example 2
Dissolving 1.14g of galanthamine hydrobromide in 25mL of N, N-dimethylformamide, dropwise adding 150mL of N, N-dimethylformamide solution containing 2.57g of pamoic acid, and stirring at 60 ℃ for reacting for 2 hours after dropwise adding; and after the reaction is finished, cooling the reaction liquid to 0-5 ℃, standing for 48 hours at the temperature, carrying out vacuum filtration, and carrying out vacuum drying for 12 hours at 50 ℃ to obtain light yellow powder, wherein the yield is 75.28%, and the purity is 99.87%.
Example 3
Dissolving 1.14g of galanthamine hydrobromide in 15mL of 1, 3-dimethyl-2-imidazolidinone, dropwise adding 150mL of 1, 3-dimethyl-2-imidazolidinone solution containing 1.17g of pamoic acid, and stirring for 10 hours at 15 ℃; and (3) standing the reaction solution in an environment at 0-5 ℃ for 24 hours, performing suction filtration, and performing vacuum drying at 50 ℃ for 2 hours to obtain light yellow powder, wherein the yield is 72.35%, and the purity is 99.83%.
Example 4
Dissolving 1.14g of galanthamine hydrobromide in 35mL of N, N-dimethylformamide, dropwise adding 200mL of N, N-dimethylformamide solution containing 5.85g of pamoic acid, stirring at 100 ℃ for reacting for 1 hour, standing the reaction solution in an environment at 5-10 ℃ for 24 hours, performing suction filtration, and performing vacuum drying at 50 ℃ for 2 hours to obtain light yellow powder, wherein the yield is 70.39%, and the purity is 99.79%.
Structure validation
The structure of the galanthamine pamoic acid salt provided by the invention is confirmed by nuclear magnetic resonance hydrogen spectroscopy, and is shown in figure 1 in detail.
1 H NMR(400MHz,DMSO-d6)：δ8.24(s,2H),8.17(d,2H),7.75(d,2H),7.63(m,2H),7.47 (m,3H),7.24(t,2H),7.12(t,3H),7.05(s,2H),4.78(s,2H),4.34(s,2H),3.83(s,3H),3.77(s, 3H),3.17(m,1H),2.93(m,2H),2.64(m,2H),1.97-1.30(m,9H)。
Solubility test
The invention examines the solubility (25 ℃) of galanthamine hydrobromide and galanthamine pamoate in water, and the specific experimental steps are as follows: respectively placing galanthamine hydrobromide and galanthamine pamoate in water, 0.01mol/L HCL solution and PBS (pH 6.8) to obtain saturated solution, shaking at 25 deg.C for 24 hr, filtering, measuring absorbance, and calculating to obtain solubility.
TABLE 1 solubility in different media (mg/mL)
Compared with galanthamine hydrobromide, the galanthamine pamoate prepared by the invention has the advantages that the solubility in water and other media is obviously reduced, and better dissolution characteristics are embodied; the lower solubility of the galanthamine derivative can improve the stability and the dissolving effect of the galanthamine compound, and also provides a raw material for developing new application of the galanthamine.
Stability survey
The invention inspects the stability of galanthamine hydrobromide and galanthamine pamoate, inspects samples under the environment of high temperature of 60 ℃, high humidity of 90% RH and illumination respectively, the specific stability test method refers to the guidance method related to stability inspection in the fourth part of Chinese pharmacopoeia 2015 edition, the purity detection is carried out by HPLC method, and the test result is shown in the following table.
TABLE 2 stability test results for galanthamine pamoate
Note: and (3) illumination test: illuminance is not less than 1.2 × 10 6 lux & hr, near ultraviolet not less than 200W & hr/m 2
The test result shows that the appearance, purity and impurity content of the galanthamine pamoate prepared by the invention are not obviously changed under the conditions of illumination, high temperature and high humidity, while the purity of the galanthamine hydrobromide serving as a reference substance is reduced under the same experimental conditions, especially in the illumination experiment, and the impurity content of the galanthamine hydrobromide is obviously increased.
Preparation of galanthamine pamoate salt tablets
Galanthamine pamoate and galanthamine hydrobromide are respectively used as active ingredients to prepare galanthamine tablets, and auxiliary materials are silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate and microcrystalline cellulose, and no sustained-release material is added.
Heating and melting the copovidone with the prescription amount, adding galanthamine pamoate or galanthamine hydrobromide, stirring uniformly, and extruding particles by using an extruder; the granules are uniformly mixed with the prescription dose of silicon dioxide, crospovidone, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate and microcrystalline cellulose, and then the tablets are tabletted, the dissolution of the tablets is detected according to pharmacopoeia standards, and the results are shown in the following table.
TABLE 3 dissolution test results for galanthamine pamoate tablet
The experimental result shows that the dissolution rate of the galanthamine hydrobromide reaches 93.2% within 1 hour, and the faster dissolution rate is shown, but the dissolution rate of the galanthamine pamoic acid salt prepared by the invention reaches 85.3% within 8 hours, and the galanthamine pamoic acid salt has slower release rate and more moderate release gradient, which also proves that the galanthamine pamoic acid salt prepared by the invention has lower solubility and better slow release effect.
Claims (9)
1. A galantamine pamoate compound having the structure shown in formula I:
wherein n is 1 or 2.
2. A process for preparing the galanthamine pamoate compound of claim 1, comprising the steps of: dissolving galanthamine hydrobromide in a certain organic solvent, dissolving pamoic acid in the same organic solvent, dropwise adding the solution into the galanthamine hydrobromide solution, heating and stirring until the reaction is finished, cooling and standing, and performing suction filtration to obtain galanthamine pamoate.
3. The method of claim 2, wherein the organic solvent is selected from the group consisting of dimethylsulfoxide, N-dimethylformamide, hexamethylphosphoric triamide, 1, 3-dimethyl-2-imidazolidinone, and combinations thereof.
4. The method for preparing the galanthamine pamoate compound as claimed in claim 2, wherein the mass-to-volume ratio of the galanthamine hydrobromide to the organic solvent is 1:10-50 g/ml.
5. The method of claim 2, wherein the molar ratio of galanthamine hydrobromide to pamoic acid is 1:1 to 5.
6. The process for preparing a galanthamine pamoate compound as claimed in claim 2, wherein the reaction temperature is from 0 ℃ to 100 ℃; the reaction time is 0.5-24 hours.
7. The method of claim 2, wherein the cooling temperature is 0-15 ℃; the cooling mode is ice bath cooling and program cooling.
8. A pharmaceutical composition characterized in that it comprises the galanthamine pamoate salt of claim 1 and other pharmaceutically acceptable ingredients.
9. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition is a spray, a tablet, a capsule, a powder injection, or a liquid injection.
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| WO2008101266A1 (en) * | 2007-02-22 | 2008-08-28 | Sanochemia Pharmazeutika Ag | Method for the production of high-purity 4a, 5, 9, 10, 11, 12,-hexahydro-6h-benzofuro [3a, 3, 2-ef] [2] benzazepine, and the derivatives thereof |
| CN101829068A (en) * | 2010-05-06 | 2010-09-15 | 徐州市光合生物营养品有限公司 | Water soluble medicament sustained-release tablets and preparation method thereof |
| CN104177368A (en) * | 2014-05-27 | 2014-12-03 | 天津梅花医药有限公司 | Galanthamine hydrobromide compound as well as preparation method and medicine compositions thereof |
| CN111233878A (en) * | 2018-11-29 | 2020-06-05 | 鲁南制药集团股份有限公司 | Galanthamine pamoate and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008101266A1 (en) * | 2007-02-22 | 2008-08-28 | Sanochemia Pharmazeutika Ag | Method for the production of high-purity 4a, 5, 9, 10, 11, 12,-hexahydro-6h-benzofuro [3a, 3, 2-ef] [2] benzazepine, and the derivatives thereof |
| CN101829068A (en) * | 2010-05-06 | 2010-09-15 | 徐州市光合生物营养品有限公司 | Water soluble medicament sustained-release tablets and preparation method thereof |
| CN104177368A (en) * | 2014-05-27 | 2014-12-03 | 天津梅花医药有限公司 | Galanthamine hydrobromide compound as well as preparation method and medicine compositions thereof |
| CN111233878A (en) * | 2018-11-29 | 2020-06-05 | 鲁南制药集团股份有限公司 | Galanthamine pamoate and preparation method thereof |
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